Reichmann, MT;
Tezera, LB;
Vallejo, AF;
Vukmirovic, M;
Xiao, R;
Reynolds, J;
Jogai, S;
... Elkington, P; + view all
(2021)
Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets.
The Journal of Clinical Investigation
, 131
(15)
10.1172/JCI148136.
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Abstract
Tuberculosis (TB) is a persistent global pandemic, and standard treatment for it has not changed for 30 years. Mycobacterium tuberculosis (Mtb) has undergone prolonged coevolution with humans, and patients can control Mtb even after extensive infection, demonstrating the fine balance between protective and pathological host responses within infected granulomas. We hypothesized that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a noninfectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared 3 primary human cell culture models at the whole transcriptome level and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified 12 intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.
| Type: | Article |
|---|---|
| Title: | Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1172/JCI148136 |
| Publisher version: | https://doi.org/10.1172/JCI148136 |
| Language: | English |
| Additional information: | This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. |
| Keywords: | Infectious disease, Pulmonology, Tuberculosis |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10131940 |
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